Project Summary: My long term goal is a career in translational research, focused on the molecular investigation and clinical treatment of prostate cancer. My immediate career goal is to develop the expertise in prostate cancer biology and clinical research that will allow me to pursue an independent career as a physician-investigator. Through a combination of didactics and mentored research experiences I will lay a groundwork in statistics, ethics, prostate tumor biology and clinical trial development that will position me to apply for and obtain funding in clinical research areas that will grow out of my current interests in the molecular effects of androgens on prostatic epithelial tissue. The research infrastructure of the Hutchinson Center and the University of Washington, the collaborative environment created by the Prostate SPORE and Program in Prostate Cancer Research, and the dual scientific and clinical mentorship provided by my mentors encompass all the resources I will need to successfully transition to an independent career. Establishing whether intraprostatic androgen levels can be suppressed to below a threshold at which essentially all prostate cancer cells undergo apoptosis has never been quantitatively addressed. In this proposal we will quantitative the pharmacologic and treatment efficacy of androgen lowering treatment strategies by measuring intraprostatic androgen levels in context of tissue and molecular correlates of tumor regression. Men with localized prostate cancer will be randomized to receive three months of neoadjuvant hormonal therapy with one of four treatments designed to progressively inhibit the androgen axis. Prostate samples obtained at diagnosis and prostatectomy will be assayed for treatment efficacy based on androgen levels, histological measures of tissue response, and assessment of androgen-regulated gene expression. Relevance: Prostate cancer is the most common cancer in American men, and the second leading cause of cancer-related death. Prostate cancer cells rely on the hormone testosterone for survival. Current methods of hormonal treatment only inhibit testicular hormone production, and ultimately fail to control the growth of prostate cancer cells. Our study will determine whether treatments inhibiting multiple sources of testosterone production (testicular, adrenal and prostatic) will be more effective than current methods in decreasing hormone levels inside the prostate, and therefore, more effective in killing prostate cancer cells.